Cognitive impairment and cortisol levels in first-episode schizophrenia patients.

Many modalities of cognition are affected in schizophrenia. The most common findings include dysfunctions of episodic and working memory and of executive functions. Although an inverse correlation between cortisol level and memory function has been proven, few studies have focused on the relationship between cortisol level and cognitive impairment in patients with schizophrenia. In an open, naturalistic, prospective study, consecutively hospitalized males diagnosed with first-episode schizophrenia, hypothalamic-pituitary-adrenal axis activity (afternoon cortisol levels, post-dexamethasone cortisol levels) was evaluated before and at the end of acute treatment. Psychopathology was assessed using the positive and negative syndrome scale (PANSS). Cognitive functions (memory, attention, psychomotor, verbal fluency, and executive functions) were tested after symptom alleviation using a neurocognitive test battery. In the total sample (n = 23), significant decreases in total PANSS score (including all subscales), afternoon cortisol levels, and post-dexamethasone cortisol levels occurred during the course of treatment. It was found that higher afternoon cortisol levels at the beginning of treatment were significantly related to impaired performance in memory functions. Afternoon cortisol levels were not significantly associated with other measured cognitive functions. No correlation was discovered between cognitive functions and post-dexamethasone cortisol levels. The determination of afternoon cortisol levels may serve to detect potential candidates for specific cognitive intervention immediately after the first psychotic breakthrough.

Brain functional connectivity of male patients in remission after the first episode of schizophrenia.

OBJECTIVES: Abnormal task-related activation and connectivity is present in schizophrenia. The aim of this study was the analysis of functional networks in schizophrenia patients in remission after the first episode. EXPERIMENTAL DESIGN: Twenty-nine male patients in remission after the first episode of schizophrenia and 22 healthy controls underwent examination by functional magnetic resonance during verbal fluency tasks (VFT). The functional connectivity of brain networks was analyzed using independent component analysis. RESULTS: The patients showed lower activation of the salience network during VFT. They also showed lower deactivation of the default mode network (DMN) during VFT processing. Spectral analysis of the component time courses showed decreased power in slow frequencies of signal fluctuations in the salience and DMNs and increased power in higher frequencies in the left frontoparietal cortex reflecting higher fluctuations of the network activity. Moreover, there was decreased similarity of component time courses in schizophrenia­the patients had smaller negative correlation between VFT activated and deactivated networks, and smaller positive correlations between DMN subcomponents. CONCLUSIONS: There is still an abnormal functional connectivity of several brain networks in remission after the first episode of schizophrenia. The effect of different treatment modalities on brain connectivity, together with temporal dynamics of this functional abnormality should be the objective of further studies to assess its potential as a marker of disease stabilization.

Prevalence of remission and recovery in schizophrenia in the Czech Republic.

OBJECTIVE: The aim of the study was to map the point prevalence of remission and recovery in patients with schizophrenia in the Czech Republic. METHOD: The point-symptomatic remission criteria were based on the definition of remission in schizophrenia according to Andreasen, without the time criterion. The definition of complete remission contained, in addition to the point-symptomatic remission criteria, a time aspect which was determined by the absence of psychiatric hospitalisation or a change in antipsychotic medications due to inefficiency in the preceding six months. Functional remission was defined by a total score on the PSP scale in the range between 71 and 100 points. Recovery was defined by the simultaneous fulfilment of the criteria for complete and functional remission. RESULTS: A total of 481 patients with schizophrenia were included in the study. The point-symptomatic remission criteria were fulfilled in a total of 258 patients (54%); complete remission occurred in a total of 214 patients (44%). Functional remission was reached by 124 patients (26%) in total. Recovery was proven in a total of 91 patients (19%). CONCLUSION: The ascertained data are in accordance with the results of methodologically similar studies and confirm the known trajectories of the course of schizophrenia.

Can repetitive transcranial magnetic stimulation be considered effective treatment option for negative symptoms of schizophrenia?

OBJECTIVE: Despite the development of second-generation antipsychotic drugs, treatment-resistant symptoms still represent a serious problem in schizophrenia. The aim of the present article was to review studies with repetitive transcranial magnetic stimulation for negative symptoms of schizophrenia and draw conclusions for clinical decision making. METHOD: Literature for this review was identified by searching MEDLINE and ISI Web of Science up to the year 2011. RESULTS: Five open studies, 13 sham-controlled studies, and 2 meta-analysis and 2 review articles were included in the present paper. The effect size of the high frequency repetitive transcranial magnetic stimulation (rTMS) over the left prefrontal cortex in the treatment of negative symptoms of schizophrenia is thought to be mild to moderate (Cohen d = 0.43-0.68). CONCLUSION: Despite the promising results of some rTMS studies, the potential of rTMS for the treatment of negative symptoms is currently relatively unclear. Large clinical studies are therefore needed, especially large multicentric studies such as depression rTMS studies.

Does repetitive transcranial magnetic stimulation have a positive effect on working memory and neuronal activation in treatment of negative symptoms of schizophrenia?

OBJECTIVE: The objective of the study was to find out whether, under the conditions of a double-blind, placebo coil controlled study, high-frequency repetitive transcranial magnetic stimulation (TMS) over the left prefrontal cortex will show positive effects on working memory with simultaneous assessment of respective changes in neuronal activation. RESULTS: Stimulation treatment led to a reduction of seriousness of negative schizophrenia symptoms in both comparative groups. However, mutual comparison of real (n=19) and sham (n=11) rTMS, respectively, has shown that the effect of real rTMS was statistically significantly higher compared with placebo stimulation. During stimulation treatment an improvement in working memory performance was also found. No statistically significant difference between the real and placebo sham rTMS, respectively, was established. The rate of neuronal activation did not change at all during rTMS treatment. CONCLUSIONS: From clinical point of view rTMS seems to be a well-tolerated neurostimulation method for treatment of negative schizophrenia symptoms with favourable of impact on cognitive functions.

Maximum-uncertainty linear discrimination analysis of first-episode schizophrenia subjects.

Recent techniques of image analysis brought the possibility to recognize subjects based on discriminative image features. We performed a magnetic resonance imaging (MRI)-based classification study to assess its usefulness for outcome prediction of first-episode schizophrenia patients (FES). We included 39 FES patients and 39 healthy controls (HC) and performed the maximum-uncertainty linear discrimination analysis (MLDA) of MRI brain intensity images. The classification accuracy index (CA) was correlated with the Positive and Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning scale (GAF) at 1-year follow-up. The rate of correct classifications of patients with poor and good outcomes was analyzed using chi-square tests. MLDA classification was significantly better than classification by chance. Leave-one-out accuracy was 72%. CA correlated significantly with PANSS and GAF scores at the 1-year follow-up. Moreover, significantly more patients with poor outcome than those with good outcome were classified correctly. MLDA of brain MR intensity features is, therefore, able to correctly classify a significant number of FES patients, and the discriminative features are clinically relevant for clinical presentation 1 year after the first episode of schizophrenia. The accuracy of the current approach is, however, insufficient to be used in clinical practice immediately. Several methodological issues need to be addressed to increase the usefulness of this classification approach.

Suicides in males after the first episode of schizophrenia.

The aim of this study was a retrospective analysis of available data on patients who committed suicide after the first episode of schizophrenia with focus on risk factors for suicide. Seven of 162 patients consecutively hospitalized at the Department of Psychiatry in Brno with first-episode schizophrenia and followed up for 10 years committed suicide by hanging (n = 4), shooting (n = 1), jumping from height (n = 1), and drowning (n = 1). All patients had more known risk factors and had visited a psychiatrist shortly before their suicide. However, according to the documentation, the patients were not asked about their intention to commit suicide and the potentially modifiable risk factors. Under the conditions of routine clinical practice, the prevention of suicide after the first psychotic episode should include early aggressive treatment and careful monitoring for suicidal behaviors in patients with known risk factors.

Repetitive transcranial magnetic stimulation and treatment of negative symptoms of schizophrenia.

One of the fundamental prerequisites of the successful schizophrenia treatment is represented by an adequately significant impact on the negative symptoms of schizophrenia. Since the present pharmacotherapy has probably reached its limit in this area, there is a logical effort to utilize other, non-pharmacological methods. One of the most promising supplements that has been for a long time verified in the clinical practice is rTMS. Most of the studies have arrived at the conclusion that rTMS is an efficient method in the treatment of negative symptoms of schizophrenia. A valuable contribution to the assessment of the rTMS application in the treatment of negative symptoms is represented by meta-analyses. The meta-analyses indicate that the effect is mild to moderate (d=0.43 to 0.68). To sum it up, there will be higher probability of the rTMS effect on negative symptoms if 10 Hz stimulating frequency and a longer stimulation period in the extent at least three, ideally four to six weeks is used.

Effect of electroconvulsive therapy on cortical excitability in a patient with long-term remission of schizophrenia: a transcranial magnetic stimulation study.

The exact effects of electroconvulsive therapy (ECT) on the brain are still not accurately known. Hypotheses considered include the effect of ECT on cortical excitability of the brain. The aim of this trial was to assess the changes in cortical excitability in the brain of a patient with remitted schizophrenia, undergoing maintenance ECT. Three successive ECT applications resulted in significant prolongation of the cortical silent period, which implies augmentation of inhibitory cortical mechanisms in the brain, most likely mediated by the GABAergic (GABA, γ-aminobutyric acid) system with direct involvement of GABAB receptors. The actual therapeutic effect of ECT is therefore probably due to facilitation of cortical inhibitory mechanisms induced by GABAergic neurotransmission.

Source-based morphometry of gray matter volume in men with first-episode schizophrenia.

OBJECTIVES: There is a lot of variability between the results of studies reporting the pattern of gray matter volume changes in schizophrenia. Methodological issues may play an important role in this heterogeneity. The aim of the present study was to replicate the better performance of multivariate "source-based morphometry" (SBM) over the mass-univariate approach. EXPERIMENTAL DESIGN: Voxel-based morphometry of Jacobian-modulated gray matter volume images, using voxel and cluster level inference, and SBM were performed in a group of first-episode schizophrenia patients (N = 49) and healthy controls (N = 127). RESULTS: Using SBM we were able to find a significant reduction of gray matter volume in fronto-temporo-cerebellar areas whereas no significant results were obtained using voxel-based morphometry. CONCLUSION: Multivariate analysis of gray matter volume seems to be a suitable method for characterization of the pattern of changes at the beginning of the illness in schizophrenia subjects.

Prolactin levels in risperidone treatment of first-episode schizophrenia.

OBJECTS: To evaluate the risperidone effect on prolactin (PRL) levels and to analyse the relation between PRL change and treatment response in first-episode schizophrenia patients. METHOD: Patients with a first-episode of schizophrenia who were consecutively admitted for hospitalisation participated in a longitudinal follow-up study that included clinical evaluation (PANSS) and PRL assessment. All patients were treated under open conditions with risperidone. RESULTS: Risperidone in an average dose lower than 4 mg significantly improved both positive and negative symptoms. Co-operating responders undergoing maintenance therapy showed a mild trend towards further long-term improvement. At the end of acute treatment the average elevation of PRL levels almost doubled the baseline value. There was a trend among responders to return to their initial values during long-term therapy. Three-quarters of the subjects had hyperprolactinaemia at the end of acute treatment (44 days), and after 1 year about one-quarter had hyperprolactinaemia. No significant correlation between PRL change and PANSS score change was found. CONCLUSION: There is a considerable variation of PRL elevation among subjects. In some patients the development of tolerance of the PRL-elevating effect was observed. Risperidone-induced changes of PRL levels may not be associated with treatment response.

Paliperidon mediated modification of cortical inhibition.

Transcranial magnetic stimulation is a neurophysiological method which enables direct quantitative in vivo assessment of cortical excitability and inhibition. The aim of the study was to assess the impact of paliperidone on the motor threshold and cortical silent period, in a drug-naive patient, with first episode schizophrenia using this technique. Paliperidone monotherapy caused a significant reduction of severity of schizophrenic symptomatology in the patient. At the same time, a significant prolongation of the cortical silent period, from 118.68 ms before to 185.13 ms after therapy, occurred. Because the cortical silent period is a function of GABA(B) receptors, we can assume that paliperidone may have the ability to enhance GABA(B) receptor-mediated neurotransmission.

Treatment of negative symptoms of schizophrenia using repetitive transcranial magnetic stimulation in a double-blind, randomized controlled study.

OBJECTIVE: To verify whether high-frequency rTMS applied above the area of the left prefrontal cortex in 15 stimulation sessions with maximum stimulation intensity is able to modify negative symptoms of schizophrenia in a double-blind, randomized controlled study. METHODS: Twenty-two patients with schizophrenia stabilized on antipsychotic medication with prominent negative symptoms were included in the trial. They were divided into two groups: eleven were treated with effective rTMS and eleven with ineffective "sham" rTMS. The ineffectiveness of the sham rTMS was achieved through the stimulation coil position. Stimulation was applied to the left dorsolateral prefrontal cortex. The stimulation frequency was 10 Hz. Stimulation intensity was 110% of the motor threshold intensity. Each patient received 15 rTMS sessions on 15 consecutive working days. Each daily session consisted of 15 applications of 10-second duration and 30-second intervals between sequences. There were 1500 stimuli per session. RESULTS: During real rTMS treatment a statistically significant decrease of negative symptoms was found (approximately 29% reduction in the PANSS negative symptom subscale and 50% reduction in the SANS). No adverse events occurred during therapy except for a mild headaches. In sham rTMS treatment a decrease of negative symptoms was also identified, but to a lesser extent than in real rTMS (about 7% in negative subscale PANSS and 13% in SANS). The change in SANS achieved statistical significance. Mutual comparison revealed a greater decrease of negative symptoms in favor of real rTMS in contrast to sham rTMS. CONCLUSION: The augmentation of rTMS enabled patients to experience a significant decrease in the severity of the negative symptoms. Our results support the therapeutic potential of rTMS at higher frequency for negative symptoms of schizophrenia.

Prefrontal but not temporal grey matter changes in males with first-episode schizophrenia.

INTRODUCTION: Changes of brain morphology are now considered as a part of the pathology of schizophrenia. Voxel-based morphometry may be used to study regional changes of the grey matter in the whole brain. It is advantageous to study first-episode patients to prevent the influence of many possible biasing factors when trying to identify primary pathological processes underlying the manifestation of the illness. OBJECTIVE: To investigate regional grey matter changes in the first-episode schizophrenia patients. METHODS: Optimized voxel-based morphometry was used to detect changes in grey matter volume in 22 patients with first-episode schizophrenia compared with 18 healthy volunteers of comparable age, gender and handedness. RESULTS: The first-episode schizophrenia group had significantly reduced grey matter volume in the prefrontal cortex (inferior and middle prefrontal gyrus, cingulate gyrus). We identified no differences in the temporal cortex. CONCLUSION: Our data support the theoretical assumption that prefrontal dysfunction underlines the primary pathology and clinical manifestation of schizophrenia. We are inclined to explain the differences in the pattern of morphological changes reported in other first-episode studies--especially the lack of changes in the temporal cortex--by heterogeneity of schizophrenia, potential progression and antipsychotic medication effect.

Neurological soft signs and their relationship to 1-year outcome in first-episode schizophrenia.

OBJECTIVES: To examine the relationship between the severity of neurological soft signs at onset and at the 1-year follow-up of patients with schizophrenia, and to investigate temporal stability of neurological soft signs within 1year from the onset of the first episode schizophrenia. METHODS: The study included 92 first-episode male schizophrenic patients. Neurological soft signs were assessed on the Neurological Evaluation Scale (NES) during index hospitalization and at a 1-year follow-up. The patients were divided into remitters and non-remitters according to their psychiatric status assessed at the 1-year follow-up, using the Positive and Negative Syndrome Scale (PANSS). RESULTS: A trend for a lower score for the NES item "others" in late remitters versus non-remitters at baseline was found during index hospitalization. At the 1-year follow-up, the overall severity of the neurological soft signs was statistically significantly higher in non-remitters than in remitters. Within 1year after index hospitalization, a significant reduction of neurological soft signs, with the exception of sensory integration, occurred in remitters. Within 1year after index hospitalization, the non-remitters reported a significant reduction of the overall NES score. CONCLUSION: These findings in a population of patients with first episode schizophrenia are in accord with the findings of previous studies which found an association between neurological soft signs, treatment response and outcome. This association may characterize a subgroup of patients with a poor course of illness and outcome. Neurological soft signs might be regarded as one of the indicators of treatment outcome in patients suffering from their first episode of schizophrenia.

Testosterone in first-episode schizophrenia.

OBJECTIVE: Recent neuroendocrinological studies have suggested that gonadal sex hormones play a significant role in the pathophysiology of schizophrenia. Low testosterone is associated with negative symptoms in chronic schizophrenia. The relevance of these findings has not yet been elucidated. The aim of our naturalistic open study was to explore the association between symptoms, drug response and testosterone levels in first-episode schizophrenia to exclude the effects of age, chronic illness, long-term treatment and institutionalization. METHODS: 68 males, consecutively hospitalised for the first time with first-episode schizophrenia were evaluated using the Positive and Negative Syndrome Scale (PANSS) on admission (before treatment) and at discharge. Further, plasma testosterone was measured. Total testosterone was assayed using chemiluminescent immunoanalysis (CMIA). All patients were treated openly by monotherapy; risperidone being the drug of first choice. Treatment response was defined as delta PANSS (PANSS total on admission - PANSS total at discharge /PANSS total on admission). RESULTS: On average the total PANSS and PANSS subscales scores significantly decreased during the acute treatment. In contrast to results in chronic schizophrenia, the mean values of testosterone were within the normal range (15.36 and 22.55 nmol/l respectively) both before and after acute treatment. The range of normal values for the method used is given as 5.76-30.43 nmol/l for males <50 years old. On admission only 6 patients had testosterone values lower than 5.76 nmol/l. No significant correlation between negative symptoms (negative PANSS subscale) at the beginning or at the end of acute treatment or between treatment response and testosterone plasma levels was found. CONCLUSIONS: During the first psychotic breakdown no significant association was observed either between total testosterone plasma levels and symptoms or treatment reactivity. However, schizophrenia is a heterogeneous disease. In some patients with first-episode schizophrenia an alteration of psychoendocrinology parameters has been observed. These patients may be more vulnerable to development of enduring negative symptoms, and pharmacotherapy based on neuroendocrinology profile should be considered.

Neurological soft signs, clinical symptoms and treatment reactivity in patients suffering from first episode schizophrenia.

OBJECTIVE: (a) To investigate the correlation between clinical symptoms and neurological soft signs in patients suffering from their first episode of schizophrenia and (b) to examine the relationship between soft signs and the reactivity of first episode treatment. METHODS: The trial included 92 male patients undergoing a first episode of schizophrenia. The clinical symptoms of the patients were rated on the positive and negative syndrome scale (PANSS). The PANSS scale was used to provide a measure for three syndromes: psychomotor poverty, disorganisation, and reality distortion. Neurological soft signs were assessed with the help of the neurological evaluation scale. RESULTS: The findings corroborated significant positive correlations between soft neurological signs on the one hand and negative symptoms and reduced treatment response on the other. CONCLUSION: Our study of the population of patients with first episode schizophrenia has corroborated the findings of those trials that found a correlation between neurological soft signs and the negative symptomatic dimension of schizophrenia. Another finding of the trial is that neurological soft signs were associated with poorer response to treatment of the first episode of schizophrenia.